The effects of 3 classes of perturbants (physical agents, pharmacologic agents, and pathologic processes) on capillary endothelial cell function will be evaluated using both in vivo and invitro techniques. A newly developed in vivo perfusion technique of the rat cortical capillary system permits the in vivo measurement of capillary endothelial cell (CEC) membrane fluidity (rigidity), using conventional and lateral-diffusion ESR techniques. The changes induced in CEC membrane fluidity by the various perturbants will be correlated to other characteristics of CEC function: permeability, active and facilitated transport activity; and enzyme activity. It is anticipated that this new application of ESR techniques will assist in the following: differentiation between micropinocytotic activity and tight junction dysfunction; elucidation of the mechanism by which the CECs may produce a dispositional tolerance to hydrophilic narcotic agonists; and, the adaptive response and altered function of the CECs to thermal stress from microwave irradiation. In addition, a variety of pathologic models (hepatic-encephalopathy, aging, diabetes, and hypertension) will be evaluated for the association between CEC membrane fluidity changes and CED function at various stages of disease progression. Membrane composition (cholesterol, phospholipids and fatty acids) of the CECs will be examined, in addition to cell viability by substrate uptake studies (radio-tracer) and O2 uptake studies (by ESR techniques). Thus, the observed changes in membrane character, by ESR techniques, will be correlated with additional parameters relevant to CEC function; in order to elucidate the response mechanisms of the CECs to the applied perturbant. It is anticipated that this proposal will provide previously unavailable information regarding perturbant induced changes in CEC function. It is hoped that these new techniques will provide information leading to a mechanistic understanding of the various perturbing agents (pathologic and pharmacologic) on the vesicular endothelium.